Process of preparing derivatives of the cyclopentanopolyhydrophenanthrene



Patented Jan. 30, 1940 PATENT OFFICE" PROCESS OF PREPARING DERIVATIVESOF THE CYCLOPENTANOPOLYHYDRO- PHENANTHRENE Max Bockmiihl, GustavEhrhart, Heinrich Ruschig, and Walter Aumiiller, Frankfort-omthe-Main-Hochst,

Germany,

Winthrop Chemical Company, Inc., New York, N. Y., a corporation of NewYork No Drawing. Application June '1, 1937, Serial no. 146,958. InGermany June 11, 1936 3 Claims.

The present invention relates to a process of preparing derivatives ofthe cyclopentanopolyhydrophenanthrene.

In U. S. application Serial No. 49,644 filed November 13, 1935, in thename of Max Bockmiihl, Gustav Ehrhart and Heinrich Ruschig a process ofpreparing ketones of polycyclic hydroaromatic compounds is describedwhich comprises subjecting to the degradation process according toCurtius compounds of the general formula wherein R stands for acyclopentanopolyhydrophenanthrene radical, and oxidizing the amineswherein R stands for a --CO0H group or for a (113 -CH.C 0 on group, by adegradation method in itself known in which the carboxyl group isseparated and an D amine is obtained as intermediate product, into thealcohol or kctone corresponding with the amine and at any stage of theprocess producing a double bond by oxidizing the hydroxyl group standingin 3-position into the keto group and subsequently treating withhalogenating agents aetiocholanyl carboxylic acid(17).

and eliminating hydrogen halide, the halogenation and dehalogenation ofsuch compounds as in 3-position contain a keto group and in thecyclopentane ring contain a CHaCHOH group or a CHaCO group, beingexcluded.

The process may for instance be carried out by oxidising in the saidacids the 3-hydroxyl group to the keto group, treating the keto-acidobtained with halogenating agents, eliminating hydrogen halide from thehalogenated, keto acids thus formed and subjecting ,the unsaturated ketoacids to a Curtius degradation process, whereby the amines formed aretransformed into the corresponding alcohols or ketones. During thisoperation the halogenated keto acids may also be dehalogenated afterthey have been transformed into the halogenated amines, hydroxy-ketonesor di-ketones formed by the degradation. The same or a similar result isattained if the said carboxylic acids are first subjected to the Curtiusdegradation method and after the oxidation of the 3-hydroxyl group tothe keto group the amines obtained are halogenated, hydrogen halide'iseliminated ifrom the halogenated amino ketones formed and theunsaturated amino compounds obtained are transformed into thecorresponding hydroxyketones or di-ketones. In this mode of operatingthe hydrogen halide need not be eliminated at the above-mentioned stageof the reaction, but may be eliminated at any further step of theoperation, for instance from the halogenated hydroxy-ketones ordi-ketones.

In the same-manner the process of the present invention may be appliedto the 3-hydroxy- In this case the sequence of the different steps ofthe reaction may likewise be varied in any desired way 'as mentionedabove.

As the acids used as parent material, such asthe bisnorlithocholic acid,may relatively readily and cheaply be obtained from bile acids the'present process is a new and industrially valuable way ofpreparingsubstances of the character of the sexual hormones.

Thev accompanying three tables of formulae illustrate the differentpossibilities of varying the process and the way of obtaining with theaid of the present process the .hormones known as progesterone andtestosterone.

2 I gasp-m cm on on.

0115 cm 6m 3 -OOOH I i (run a a. Tabb 1!.)

cm om om 1 1-0001:

I 1 1&

cm on. em

JJ-NHI IA cm on. em U$IO Table" In OH; H:

OH: OH: OH:

(B-N'Humhte M1:

on. on. cm Ji-Nflmcahte OH: OH:

JJ-NHmoatate 3* OH; OH:

name Table H-Conflnu'ad CHI OH:

Table III-Continued The following examples serve to illustrate theinvention, but they are not intended to limit it thereto:

(1) 18 grams of acetyl-bisnorlithocholic acid which may be prepared withapplication of the.

process described in U. S.'application Serial No. 98,402 filed August28, 1936 in the name oiMax Bockmiihl, Gustav Ehrhart and HeinrichRuschig are transformed into the acid chloride by means of three timestheir weight of thionyl chloride as described in U. S. applicationSerial No. 49,644

filed November 13, 1935, in the name of Max Bockmiihl, Gustav Ehrhartand Heinrich Ruschlg and the azlde, iso-cyanate and amine are preparedfrom the acid chloride also as therein described.

10 grams of the amine acetate are then dissolved in glacial acetic acidand 2.64 grams ofchromic acid (1.5 0) in glacial acetic acid are causedslowly to flow into this solution. The oxidation solution is allowed tostand'for 24 hours at 15C. The small excess of chromic acid is thendestroyed with the aid of zinc dust, the solution is concentrated underreduced pressure and water is added. The amine is set free by means of asolution or sodium carbonate and the mixture is extracted with ether.From the dry ethereal solution the 3-oxo-ternorcholanyl amine isprecipitated in the form oi. the acetate.

5 grams of this oxo-amine are dissolved in glacial acetic acid and aftersome drops of hydrobromic acid have beenadded a solution oi. 2.12

' grams of bromine (=1 mol) in glacial acetic acidis caused to flow intothe solution. The latter is at once decolorized and hydrogen bromideescapes. 5 grams of silver acetate are then added to the solution, thewhole is made up to 600 cc. and heated in a reflux apparatus. After 45minutes the separation of silver halide is finished. The solution of theunsaturated oxoamine obtained is filtered and transformed into theprogesterone as described in the above named U. S. application SerialNo. 49,644. During this operation the hydrochloric acid may be sepa--rated not only with the aid 01 pyridine but likewise with the aid 0!sodium alcoholate.

If the solution of 5 grams of oxo-amine and 2.12 grams of brominereferred to above is boiled for 2 hours in a reflux apparatus together.with an alcoholic alkali lye chiefly the3-oxo-4-hydroxy-ternorcholanyl-amine is obtained.

(2) 5 grams of 3-acetoxyaetiocholanyl carboxylic acid (19) aretransformed into the corresponding chloride as described in the U. S.application Serial No. 132,635 filed March 23, 1937, in the name of MaxBockmiihl, Gustav Ehrhart and Heinrich Ruschig, which is decomposed soas to obtain the corresponding amine.

A solution of 0.85 grams of chromic acid (1.5 0) in glacial acetic acidis caused to flow into a solution 01. 3 grams ofhydroxyaetiocholanyl-amine-acetate i'n glacial acetic acid and themixture is allowed to stand for 24 hours at 15 C. After zinc dust hasbeen added the small excess of chromlc acid is destroyed, the solutionis evaporated under reduced pressure, water is added to the residuewhich is rendered alkaline by means of a solution of sodium carbonateand thefree oxo-amine is extracted with ether. Aiter the etherealsolution has been dried the 0x0- amine is precipitated in the form ofthe acetate.

1.5 grams of the 3-oxo-aetiocholanyl-amine acetate are then dissolved inglacial acetic acid, some drops of hydrobromic acid are added to thesolution and 0.69 gram of bromine in 10 cc;

of glacial acetic acid is introduced drop by drop. The solution isevaporated under reduced pressure, the residue is dissolved in alcoholand the amino group of the. 3-oxo-4-bromaetiocholanylaid of an oxidizingagent and producing a double 1. The process which comprises transforminga saturated acid of the general formula wherein stands for a member ofthe group consisting of -coon and -t H-COOH by means of the Curtiusdegradation method into the corresponding amine, oxidizing the 3-hydroxyl group into the keto group with the transforming the acidchloride into the acid azide with the aid of sodium azide, heating theazide and saponifying the isocyanate thus formed with the aid of an acidso as to obtain the corresponding amine, oxidizing this amine withchromic acid to the 3-oxo-ternorcholany1 amine, causing bromine to actupon said compound and debrominating the compound thus formed by meansof silver acetate.

3. The process which comprises oxidizinghydroxy-aetiocholanyl-amine-acetate with chromic acid in the presence ofglacial acetic acid, causing bromine to act upon the3-oxo-aetiocholanylamine-acetate thus formed, transforming this amineinto the corresponding bydroxyl compound by causing it to react withnitrous acid means of silver acetate.

MAX 1! o :1.. I L GUSTAV EHRHART.

.CERTIFiCATE 0 CORRECTION. Patent No. 2,188,370. January 301191 mxBOCKMUHL, ET AL;

It is hereby certifieothat error appears in the printed specification ofthe'above numbered patent requiring: correc tiona-e follows: Page 14;,line 56, Tab1.e-III, below the row of three formulae in line s 25 to 5strike out the word "Testosterone" and insert the same in lin efitbelowthe mid.- dle formula in eaid row of three; and that the saidLetters Petent should be reaq. with this cor'rection therein that thesame may conform to the rec- V 0rd of the case in the-:PatentYOIffice.

Signed and sealed this 2nd da' of July A. 1). 191m.

Henry'van Arsdale (Seal) Acting Commissioner of Patents.

